Evidence that Increased Acetaminophen use in Genetically Vulnerable Children

It appears that the marked increase in the rate of autism, asthma, and attention
deficit with hyperactivity throughout much of the world may be largely caused
by the marked increase in the use of acetaminophen in genetically and/or
metabolically susceptible children, and the use of acetaminophen by pregnant
women. Toxicity of acetaminophen may cause autism by overloading the
defective sulfation pathway catalyzed by phenolsulfotransferase, which is
deficient in autism, leading to overproduction of the toxic metabolite
N-acetyl-p-benzoquinone imine (NAPQI). Increased levels of NAPQI reduce the
ability to detoxify a host of toxic chemicals in the environment, increasing
oxidative stress, which leads to protein, lipid, and nucleic acid damage from
free radicals. Epidemiological evidence also supports the association of
increased acetaminophen usage with autism, asthma, and attention deficit with
hyperactivity. The marked increases in the incidences of autism, asthma, and
attention deficit disorder in the United States coincide with the replacement
of aspirin by acetaminophen in the 1980s. The characteristic loss of Purkinje
cells in the brains of people with autism is consistent with depletion of brain
glutathione due to excess acetaminophen usage, which leads to premature brain
Purkinje cell death. The anomalous hair mercury concentrations of children with
autism are consistent with exposure of growing hair proteins to NAPQI derived
from acetaminophen, which competitively inhibits the reaction of mercury with
hair sulfhydryl groups. Finally, large-scale faulty production of acetaminophen
products, such that the labeled values were exceeded by the true concentrations,
in addition to contamination with bacteria and tribromoanisole, may have greatly
increased the chances of children receiving overdosages of acetaminophen and
potential toxins for perhaps as long as a decade.

One of the puzzling aspects of autism is the marked increase in the incidence of
autism that began in the United States in the early 1980s and has appeared to
increase continuously since then. The highest incidence of autism has been
reported to be South Korea, where the incidence is now reported to be one in
38 boys.1 Increased incidence of autism due to more effective diagnosis was
disproved in the study of Irva Hertz-Picciotto who showed that perhaps 12% of the
increased autism diagnoses could be attributed to improved diagnosis.2 A wide
range of environmental factors has been associated with increased autism
incidence, including pesticides, chemicals, phthalates, polychlorinated
biphenyls, solvents, heavy metals or other pollutants.3 Although toxic chemicals
are undoubtedly not beneficial for the health of any person, is there any
information that indicates that a toxic avalanche of chemicals inundated the
United States in the early 1980s? Indeed a wealth of knowledge about environmental
chemicals has led to marked reductions in exposure to chemicals such as lead and
dichlorodiphenyltrichloroethane (DDT) in the United States over the past 50 years.
For example, acceptable safe limits for levels of lead in the blood have
decreased from 60 μg/dL in 1960 to <5 μg/dL in 2010.4

Introduction

Making a connection between disease appearance and causative agent is important.
Clinical studies, epidemiological studies and post-market pharmacovigilence are
of utmost importance in recognizing signals and drug-induced side effects. One
of the most notable cases of serious adverse effects caused by a pharmaceutical
agent was the terrible developmental epidemic of the birth of children with
seal-like arms and legs (phocomelia) that was linked to the maternal use of the
sedative thalidomide 20–35 days after conception.5 What would have happened if
the thalidomide connection had never been made? One of the difficulties with
chemical studies of autism associations is that most chemicals are used
worldwide, making it difficult to find a “clean” environment where autism might
be less prevalent. One of the clues that led to the discovery of thalidomide as
the causative agent of deformed limbs was that it was much more commonly used in
Europe than in the United States. Countries with the greatest use of thalidomide
by pregnant women during pregnancy were those with the highest incidence of
deformed babies. If there was a geographic region in the world in which the
incidence of autism was much lower than that in the United States, a comparison
of medical or dietary differences might provide a significant clue to the major
cause of autism. Such a country is Cuba. The highest estimate of the total
incidence of autism in Cuba is 185 cases out of a total population of 11,000,000
(0.00168% of the population) compared with an estimate of as high as 1.5 million
in a total United States population of 300 million (0.50%).6, 7 The percentage
of the population with autism in the United States is thus 298 times higher than
that in Cuba. Cuba is much more economically challenged than the United States,
with the per capita income of Cuba approximately eight times lower than that in
the United States. Despite the economic challenges presented to the communist
government of Cuba, basic healthcare is readily available and there are a large
number of physicians trained in 14 different medical schools. Unlike the United
States, where vaccines are optional in many states, vaccines are compulsory in
Cuba and Cuba has one of the most highly vaccinated populations in the world
against a wide variety of infectious agents.8 For example, the vaccination rate
for measles was reported to be 99.7%. The association of autism with various
vaccines has had a very controversial history with inflamed passions on both
sides of the debate and will not be examined here.

However, a topic much less frequently addressed in association with autism is
the therapies that are given in conjunction with vaccines. The practice of
prescribing acetaminophen as a prophylactic fever preventative is widespread in
the United States but is very uncommon in Cuba (personal communications, Dr
Olympio Rodriquez Santos MD, MSc, Allergist, Camaguey, Cuba). In the United States,
some physicians have started to advise parents to begin to take acetaminophen
prophylactically daily 5 days prior to childhood vaccines; some children on such
prophylactic treatment had an autistic regression that began prior to
vaccination (personal communication, Kerry Scott Lane MD, Anesthesiologist, West
Palm Beach, Florida, USA). In Cuba, acetaminophen is not approved as an
over-the-counter (OTC) product, however, it has been available as an OTC product
since 1959 in the United States. Furthermore, in Cuba, prophylactic use of
antipyretic drugs is not the standard medical treatment for vaccine-related
fever (personal communications with Dr Olympio Rodriquez Santos). If high fever
continues after vaccination in Cuba for more than 2 days, the parents are
advised to visit the physician’s office where the drug metamizole is most
commonly prescribed. Prescription of acetaminophen in such cases is rare.
Metamizole is used in many countries throughout the world but is banned in the
United States and some other countries because of a rare association with
agranulocytosis.9